Clinical characteristics of patients with spinocerebellar ataxias 1, 2, 3 and 6 in the US; a prospective observational study

Abstract

BackgroundAll spinocerebellar ataxias (SCAs) are rare diseases. SCA1, 2, 3 and 6 are the four most common SCAs, all caused by expanded polyglutamine-coding CAG repeats. Their pathomechanisms are becoming increasingly clear and well-designed clinical trials will be needed.MethodsTo characterize the clinical manifestations of spinocerebellar ataxia (SCA) 1, 2, 3 and 6 and their natural histories in the United States (US), we conducted a prospective multicenter study utilized a protocol identical to the European consortium study, using the Scale for the Assessment and Rating of Ataxia (SARA) score as the primary outcome, with follow-ups every 6 months up to 2 years.ResultsWe enrolled 345 patients (60 SCA1, 75 SCA2, 138 SCA3 and 72 SCA6) at 12 US centers. SCA6 patients had a significantly later onset, and SCA2 patients showed greater upper-body ataxia than patients with the remaining SCAs. The annual increase of SARA score was greater in SCA1 patients (mean ± SE: 1.61 ± 0.41) than in SCA2 (0.71 ± 0.31), SCA3 (0.65 ± 0.24) and SCA6 (0.87 ± 0.28) patients (p = 0.049). The functional stage also worsened faster in SCA1 than in SCA2, 3 and 6 (p = 0.002).ConclusionsThe proportions of different SCA patients in US differ from those in the European consortium study, but as in the European patients, SCA1 progress faster than those with SCA2, 3 and 6. Later onset in SCA6 and greater upper body ataxia in SCA2 were noted. We conclude that progression rates of these SCAs were comparable between US and Europe cohorts, suggesting the feasibility of international collaborative clinical studies.

Targeting potassium channels to treat cerebellar ataxia

“…Retrospective review of patient records and unblinded assessments in patients are, however, susceptible to bias. Given the duration of follow‐up, and the sustained improvements in patients where the natural history of disease is progressive,63, 64 our findings in patients are encouraging for the utility of potassium channel activators in the treatment of symptoms in patients with SCA. It is possible that changes in Purkinje neuron membrane excitability are present in many etiologies of SCA, and that the ion channel targets of chlorzoxazone and baclofen are relevant targets in these SCAs as well.…”

Current molecular insight to reveal the dynamics of CAG repeating units in spinocerebellar ataxia

“…It is also a common subtype of SCA and is characterized by cerebellar ataxia, dysarthria, and Nystagmus, with very slow progression that is the hallmark feature of this subtype (22 In study of cell culture models of this disease it presented early apoptotic cell death. Voltage-dependent calcium channels are the hetero-oligomeric proteins that comprise pore-forming α1 and auxiliary β, α2 and δ and in some tissues γ subunits (23,24).…”

Spinocerebellar ataxia 1: case and cohort-based studies in India

“…In fact, such cohort-based studies have indicated the influence of factors other than polyQ size to affect disease onset in SCA1 18,32 . Another cohort-based study has shown the lack of correlation between CAG repeat size and disease progression, indicating the influence of other confounding factors after disease onset 17 . Thus, cohort-based studies are necessary for understanding all factors that lead to disease characteristics and progression in SCA1 individuals.…”

“…Specific cohortbased studies on the natural history and clinical characteristics of SCAs are gaining importance because such studies could help in understanding the preclinical stages of SCA, where therapy is likely to be most effective. Such cohort-based studies exploring the clinical and biological characteristics of at-risk cases of SCA1 have so far been conducted in the US, Europe, South Africa [16][17][18] and more recently in India 19 .…”